Azathioprine
Vue d'ensemble
Description
L’azathioprine est un médicament immunosuppresseur utilisé principalement pour prévenir le rejet de greffe d’organe et pour traiter les maladies auto-immunes telles que la polyarthrite rhumatoïde, la maladie de Crohn et le lupus érythémateux disséminé . Il a été synthétisé pour la première fois en 1956 par Gertrude Elion, William Lange et George Hitchings . L’this compound est un promédicament qui est converti en 6-mercaptopurine dans l’organisme, qui interfère ensuite avec la synthèse des purines, inhibant ainsi la prolifération des cellules, en particulier celles du système immunitaire .
Mécanisme D'action
L’azathioprine exerce ses effets en étant convertie en 6-mercaptopurine dans l’organisme . La 6-mercaptopurine est ensuite métabolisée en métabolites actifs qui inhibent la synthèse des purines. Cette inhibition entraîne une réduction de la prolifération des cellules à division rapide, en particulier celles du système immunitaire . Les principales cibles moléculaires de l’this compound comprennent les enzymes impliquées dans la synthèse des purines, telles que l’hypoxanthine-guanine phosphoribosyltransférase et la thiopurine S-méthyltransférase . Ces voies conduisent finalement à la suppression de la réponse immunitaire .
Méthodes De Préparation
L’azathioprine est synthétisée par un processus en plusieurs étapes. La principale voie de synthèse implique la réaction de la 6-mercaptopurine avec le 1-méthyl-4-nitro-5-imidazole . Les conditions réactionnelles comprennent généralement l’utilisation d’un solvant tel que le diméthylformamide et d’une base telle que l’hydroxyde de sodium. La réaction se poursuit par la formation d’un intermédiaire, qui est ensuite cyclisé pour former l’this compound .
Les méthodes de production industrielle de l’this compound impliquent des voies de synthèse similaires mais sont optimisées pour la production à grande échelle. Cela inclut l’utilisation de réacteurs à écoulement continu et de systèmes automatisés pour assurer une qualité et un rendement constants .
Analyse Des Réactions Chimiques
L’azathioprine subit plusieurs types de réactions chimiques, notamment :
Oxydation : L’this compound peut être oxydée pour former divers métabolites.
Réduction : Le groupe nitro de l’this compound peut être réduit en groupe amino dans certaines conditions.
Substitution : L’this compound peut subir des réactions de substitution nucléophile, en particulier au niveau de l’atome de soufre.
Les réactifs et les conditions courants utilisés dans ces réactions comprennent des agents oxydants comme le peroxyde d’hydrogène pour l’oxydation et des agents réducteurs comme le borohydrure de sodium pour la réduction . Les principaux produits formés à partir de ces réactions comprennent l’acide 6-thiourique et divers dérivés substitués de l’this compound .
Applications de la recherche scientifique
L’this compound a une large gamme d’applications de recherche scientifique :
Applications De Recherche Scientifique
Azathioprine has a wide range of scientific research applications:
Comparaison Avec Des Composés Similaires
L’azathioprine fait partie de la classe des médicaments thiopuriniques, qui comprend également la 6-mercaptopurine et la thioguanine . Comparée à ces composés, l’this compound possède une structure unique qui comprend un cycle imidazole supplémentaire lié à l’atome de soufre . Cette différence structurelle confère à l’this compound un profil pharmacocinétique distinct et la rend plus adaptée à certaines applications cliniques .
Composés similaires
6-Mercaptopurine : Utilisée principalement dans le traitement de la leucémie et des maladies auto-immunes.
Thioguanine : Utilisée dans le traitement de la leucémie myéloïde aiguë.
Méthotrexate : Un autre médicament immunosuppresseur utilisé dans le traitement du cancer et des maladies auto-immunes.
La structure et le mécanisme d’action uniques de l’this compound en font un médicament précieux dans le traitement de diverses affections auto-immunes et dans la prévention du rejet de greffe d’organe .
Propriétés
IUPAC Name |
6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purine |
Source
|
|---|---|---|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI |
InChI=1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13) |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
InChI Key |
LMEKQMALGUDUQG-UHFFFAOYSA-N |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Canonical SMILES |
CN1C=NC(=C1SC2=NC=NC3=C2NC=N3)[N+](=O)[O-] |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Molecular Formula |
C9H7N7O2S |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
| Explanation | CAMEO Chemicals and all other CAMEO products are available at no charge to those organizations and individuals (recipients) responsible for the safe handling of chemicals. However, some of the chemical data itself is subject to the copyright restrictions of the companies or organizations that provided the data. | |
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Related CAS |
55774-33-9 (hydrochloride salt) |
Source
|
| Record name | Azathioprine [USAN:USP:INN:BAN:JAN] | |
| Source | ChemIDplus | |
| URL | https://pubchem.ncbi.nlm.nih.gov/substance/?source=chemidplus&sourceid=0000446866 | |
| Description | ChemIDplus is a free, web search system that provides access to the structure and nomenclature authority files used for the identification of chemical substances cited in National Library of Medicine (NLM) databases, including the TOXNET system. | |
DSSTOX Substance ID |
DTXSID4020119 |
Source
|
| Record name | Azathioprine | |
| Source | EPA DSSTox | |
| URL | https://comptox.epa.gov/dashboard/DTXSID4020119 | |
| Description | DSSTox provides a high quality public chemistry resource for supporting improved predictive toxicology. | |
Molecular Weight |
277.27 g/mol |
Source
|
| Source | PubChem | |
| URL | https://pubchem.ncbi.nlm.nih.gov | |
| Description | Data deposited in or computed by PubChem | |
Physical Description |
Azathioprine appears as pale yellow crystals or yellowish powder. Decomposes at 243-244 °C. Used for the treatment of rheumatoid arthritis. A known carcinogen., Solid |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Solubility |
>41.6 [ug/mL] (The mean of the results at pH 7.4), less than 1 mg/mL at 73 °F (NTP, 1992), Insoluble, Very slightly soluble in ethanol and chloroform; sparingly soluble in dilute mineral acids; soluble in dilute alkali solutions, Insoluble in water, 1.07e+00 g/L |
Source
|
| Record name | SID26670994 | |
| Source | Burnham Center for Chemical Genomics | |
| URL | https://pubchem.ncbi.nlm.nih.gov/bioassay/1996#section=Data-Table | |
| Description | Aqueous solubility in buffer at pH 7.4 | |
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
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| Record name | Azathioprine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00993 | |
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| Record name | AZATHIOPRINE | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Mechanism of Action |
Azathioprine's mechanism of action is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells. 6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis. This may be mediated through rac1's action on mitogen-activated protein kinase, NF-kappaB., Following exposure to nucleophiles ... azathioprine is cleaved to 6-mercaptopurine which, in turn, is converted to additional metabolites that inhibit de novo purine synthesis. 6-Thio-IMP, a fraudulent nucleotide, is converted to 6-thio-GMP and finally to 6-thio-GTP, which is incorporated into DNA and gene translation is inhibited. Cell proliferation is prevented, inhibiting a variety of lymphocyte functions., Azathioprine (AZA), one of the antimetabolite drugs, is a purine analog that is more potent than the prototype 6-mercaptopurine, as an inhibitor of cell replication. Immunosuppression likely occurs because of the ability of the drug to inhibit purine biosynthesis. ... Although T-cell functions are the primary targets for this drug, inhibition of /(natural killer cells)/ NK function and macrophage activities has also been reported., Azathioprine inhibits DNA synthesis and, as a purine antimetabolite, exerts its effect on activated lymphocytes, which requires purines during their proliferative phase. It inhibits both cellular and humoral responses, but does not interfere with phagocytosis or interferon production. It is a nonspecific cytotoxic agent. Its immunosuppressive effect is believed to be due to mercaptopurine, to which it is metabolized., The exact mechanism of immunosuppressive action is unknown since the exact mechanism of the immune response itself is complex and not completely understood. The immunosuppressive effects of azathioprine involve a greater suppression of delayed hypersensitivity and cellular cytotoxicity tests than of antibody responses. Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins; it may also interfere with cellular metabolism and inhibit mitosis., For more Mechanism of Action (Complete) data for AZATHIOPRINE (6 total), please visit the HSDB record page. |
Source
|
| Record name | Azathioprine | |
| Source | DrugBank | |
| URL | https://www.drugbank.ca/drugs/DB00993 | |
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| Record name | AZATHIOPRINE | |
| Source | Hazardous Substances Data Bank (HSDB) | |
| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7084 | |
| Description | The Hazardous Substances Data Bank (HSDB) is a toxicology database that focuses on the toxicology of potentially hazardous chemicals. It provides information on human exposure, industrial hygiene, emergency handling procedures, environmental fate, regulatory requirements, nanomaterials, and related areas. The information in HSDB has been assessed by a Scientific Review Panel. | |
Color/Form |
Pale yellow crystals from 50% aq acetone | |
CAS No. |
446-86-6 |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Azathioprine | |
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| Record name | Azathioprine [USAN:USP:INN:BAN:JAN] | |
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| Record name | Azathioprine | |
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| URL | https://www.drugbank.ca/drugs/DB00993 | |
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| Record name | azathioprine | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
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Melting Point |
469 to 471 °F (decomposes) (NTP, 1992), dec 243-244 °C, 243.5 °C |
Source
|
| Record name | AZATHIOPRINE | |
| Source | CAMEO Chemicals | |
| URL | https://cameochemicals.noaa.gov/chemical/19837 | |
| Description | CAMEO Chemicals is a chemical database designed for people who are involved in hazardous material incident response and planning. CAMEO Chemicals contains a library with thousands of datasheets containing response-related information and recommendations for hazardous materials that are commonly transported, used, or stored in the United States. CAMEO Chemicals was developed by the National Oceanic and Atmospheric Administration's Office of Response and Restoration in partnership with the Environmental Protection Agency's Office of Emergency Management. | |
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| Record name | Azathioprine | |
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| URL | https://www.drugbank.ca/drugs/DB00993 | |
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| Record name | AZATHIOPRINE | |
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| URL | https://pubchem.ncbi.nlm.nih.gov/source/hsdb/7084 | |
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| Record name | Azathioprine | |
| Source | Human Metabolome Database (HMDB) | |
| URL | http://www.hmdb.ca/metabolites/HMDB0015128 | |
| Description | The Human Metabolome Database (HMDB) is a freely available electronic database containing detailed information about small molecule metabolites found in the human body. | |
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Synthesis routes and methods
Procedure details
Retrosynthesis Analysis
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| Template Set | Pistachio/Bkms_metabolic/Pistachio_ringbreaker/Reaxys/Reaxys_biocatalysis |
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Feasible Synthetic Routes
Q1: How does Azathioprine exert its immunosuppressive effect?
A1: this compound acts as a prodrug, metabolizing into 6-mercaptopurine (6-MP). [] 6-MP undergoes further transformations, ultimately forming active thioguanine nucleotides (6-TGNs). [] These 6-TGNs are responsible for the immunosuppressive effect by incorporating into DNA and inhibiting purine synthesis, disrupting DNA and RNA synthesis, thereby primarily affecting rapidly proliferating cells like lymphocytes. []
Q2: Can you elaborate on the role of 6-Thio-GTP, a metabolite of this compound, in immunosuppression?
A2: 6-Thio-GTP, generated from this compound, plays a crucial role in immunosuppression by inhibiting the activation of Rac1 and Rac2 GTPases in T cells. [] This inhibition disrupts the Vav1-Rac signaling pathway, essential for T cell activation and function. []
Q3: What is the significance of Ezrin-Radixin-Moesin proteins in this compound's mechanism?
A3: this compound, through its metabolite 6-Thio-GTP, blocks the dephosphorylation of Ezrin-Radixin-Moesin (ERM) proteins in T cells by inhibiting Vav1 exchange activity on Rac proteins. [] This blockade of ERM dephosphorylation ultimately disrupts the formation of a stable interaction between T cells and antigen-presenting cells (APCs), known as the immunological synapse, hindering T cell activation and proliferation. []
Q4: What is the molecular formula and weight of this compound?
A4: The molecular formula of this compound is C9H7N7O2S, and its molecular weight is 277.27 g/mol.
Q5: Is there information available on this compound's material compatibility or stability under various conditions within the provided research?
A5: The provided research papers primarily focus on the clinical aspects and applications of this compound. They do not delve into material compatibility and stability studies.
Q6: Does this compound exhibit catalytic properties?
A6: this compound is not known to possess catalytic properties. It functions as an immunosuppressive agent by interfering with DNA synthesis and cellular processes rather than catalyzing chemical reactions.
Q7: Has computational chemistry been employed to study this compound?
A7: While the provided research papers primarily focus on clinical studies, one paper mentions computational approaches. [] The study suggests using computational methods for dosage determination to avoid toxicity or undertreatment of drugs like mercaptopurine and this compound. []
Q8: What are the challenges associated with this compound formulation, and how can they be addressed?
A9: While not explicitly discussed in the papers, one study focuses on developing this compound tablets for colon-targeted delivery. [] This suggests challenges related to its absorption and potential degradation in the upper gastrointestinal tract. The study explores using Eudragit-S, Eudragit-L, and cellulose acetate phthalate coatings to achieve colon-targeted release, highlighting the role of formulation strategies in enhancing this compound delivery. []
Q9: Is there information available regarding SHE regulations specific to this compound in the provided research?
A9: The provided research predominantly centers on clinical findings and doesn't encompass specific SHE regulatory information concerning this compound.
Q10: How is this compound metabolized in the body?
A11: this compound is metabolized in a complex pathway. Initially, it's converted to 6-mercaptopurine, which then undergoes various transformations. One crucial enzyme involved is Thiopurine methyltransferase (TPMT). [, , , ]
Q11: Why is TPMT crucial in this compound therapy?
A12: TPMT plays a vital role in inactivating 6-mercaptopurine, a metabolite of this compound. [, , , , ] Individuals with low TPMT activity may experience a buildup of thioguanine nucleotides, leading to severe myelosuppression. [, , ] Therefore, assessing TPMT activity before and during therapy is crucial for guiding dosage and preventing toxicity. [, , , ]
Q12: How does this compound's metabolism influence its dosing?
A13: this compound's complex metabolism, particularly its dependence on TPMT activity, necessitates personalized dosing. [, , ] Patients with low TPMT activity require significantly reduced doses to avoid life-threatening myelosuppression. [, , ] Monitoring leukocyte and platelet counts alongside thioguanine nucleotide concentrations is crucial for dose adjustment. []
Q13: Are there factors beyond TPMT that affect this compound's effectiveness?
A14: Yes, while TPMT is critical, other factors influencing this compound's disposition include drug interactions and patient characteristics. For example, Allopurinol inhibits xanthine oxidase, another enzyme involved in mercaptopurine metabolism, impacting this compound's effects. [] Additionally, age, sex, and renal function can affect TPMT activity and, consequently, this compound's action. []
Q14: Can you provide specific examples of this compound's efficacy from the provided research?
A14: The research highlights this compound's efficacy in several clinical scenarios:
- Ulcerative Colitis: A study demonstrated that this compound maintenance therapy effectively prevents relapse in patients with ulcerative colitis who achieved remission while on the drug. [] This finding has significant implications for managing this chronic condition.
- Crohn's Disease: this compound proved beneficial in preventing postoperative recurrence of Crohn's disease. [] A systematic review highlighted a reduced risk of both clinical and severe endoscopic recurrence with this compound or 6-mercaptopurine use after surgery. []
Q15: Is there information on this compound resistance mechanisms in the research papers?
A15: The research papers provided do not delve into specific this compound resistance mechanisms.
Q16: What are the known side effects of this compound?
A16: While the focus is on scientific aspects, the papers do mention some side effects observed in clinical settings:
- Myelosuppression: This is a significant concern, particularly in individuals with low TPMT activity. [, , ] It manifests as a reduction in blood cell counts, potentially leading to leukopenia, anemia, and thrombocytopenia.
- Gastrointestinal Issues: Gastrointestinal symptoms are reported, and while not detailed, they are often a reason for discontinuing treatment. []
- Hepatotoxicity: this compound can potentially cause liver damage, evident through elevated liver enzyme levels. [, ]
- Pancreatitis: this compound-induced pancreatitis is a rare but serious adverse effect. [, ]
Q17: Are there strategies to enhance this compound's delivery to specific targets?
A18: One of the research papers investigates delivering this compound specifically to the colon. [] The researchers achieved this by coating this compound tablets with Eudragit-S, Eudragit-L, and cellulose acetate phthalate polymers. [] This approach aims to bypass absorption in the upper gastrointestinal tract, potentially reducing side effects and improving drug delivery to the colon, which is relevant for treating inflammatory bowel diseases.
Q18: What biomarkers are crucial for this compound therapy?
A18: Monitoring specific biomarkers is crucial during this compound treatment:
- Thiopurine methyltransferase (TPMT) activity: Measuring TPMT activity before and during treatment helps personalize dosage and minimize the risk of severe myelosuppression. [, , , ]
- Blood Cell Counts: Regular monitoring of leukocyte and platelet counts helps detect myelosuppression early on. []
- Thioguanine Nucleotide (6-TGN) Levels: Measuring 6-TGN levels can help optimize the dosage and balance efficacy with the risk of toxicity. []
Q19: What analytical methods are used to characterize and quantify this compound?
A19: The research papers primarily focus on the clinical aspects and do not provide detailed descriptions of specific analytical methods used for this compound characterization and quantification.
Q20: Is there information on this compound's environmental impact or degradation in the provided research?
A20: The environmental impact and degradation of this compound are not discussed in the provided research papers.
Q21: Do the papers provide details on analytical method validation or quality control measures for this compound?
A21: The provided research primarily focuses on clinical findings and does not include specifics regarding analytical method validation, quality control, or assurance for this compound.
Q22: Does this compound induce an immune response itself?
A22: The provided research papers do not delve into this compound's potential to induce an immune response (immunogenicity).
Q23: What is known about this compound's interaction with drug transporters or drug-metabolizing enzymes?
A25: One crucial interaction highlighted is the impact of Allopurinol on this compound's metabolism. [] Allopurinol, often used to treat gout, inhibits xanthine oxidase, an enzyme involved in mercaptopurine (this compound's metabolite) breakdown. [] This interaction can increase the risk of this compound toxicity, particularly myelosuppression, by increasing 6-mercaptopurine levels.
Q24: Is there information on this compound's biocompatibility and biodegradability within the provided research?
A24: The provided research papers do not explicitly address this compound's biocompatibility and biodegradability.
Q25: Are there alternatives to this compound for the conditions discussed, and how do they compare?
A25: The provided research does mention some alternatives to this compound:
- Mycophenolate Mofetil (MMF): MMF is another immunosuppressive agent. One study compared this compound and MMF for kidney transplant recipients and found that while MMF reduced acute rejection, it did not show a significant advantage over this compound in preventing graft loss. []
- Cyclosporine: This immunosuppressant is often used in transplantation. Research indicates that while cyclosporine is effective, it might carry a higher risk of certain side effects like impaired fibrinolytic activity compared to this compound. []
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